Stable bismuth tribromophenate ointment and process of preparation

ABSTRACT

AN EFFECTIVE OINTMENT FOR THE TREATMENT OF BURNS IS BISMUTH TRIBROMOPHENATE IN AN OLEAGINOUS OINTMENT BASE. HOWEVER THE COMPOSITION HAS THE DISADVANTAGE THAT IT IS UNSTABLE AND THE BUSMUTH COMPOUND DOES NOT REMAIN IN SUSPENSION. A STABLE SUSPENSION OF BISMUTH TRIBROMOPHENATE IN AN OLEAGINOUS OINTMENT BASE IS PROVIDED HEREIN.

Unitcd States Patent 3,592,909 STABLE BISMUTH TRIBROMOPHENATE OINT- MENTAND PROCESS OF PREPARATION Eason G. Pritchard, P.O. Box 2506, Knoxville,Tenn. 37902 No Drawing. Filed June 24, 1968, Ser. No. 739,137 Int. Cl.A611: 9/00, 9/06 US. Cl. 424-296 7 Claims ABSTRACT OF THE DISCLOSUREBACKGROUND OF THE INVENTION This invention involves improvements incompositions for treating burns, that is, tissue injuries caused bythermal, electrical, radioactive, or chemical agents.

The common mechanism in burning is denaturation of protein, resulting incell injury or cell death. Burns are always accompanied by edema, acollection of fluid or exudate beneath the traumatized skin area. Thelayers of the skin involved are destroyed by coagulation necrosis.During the second twenty-four hours after the burn the development ofedema and exudate progressively lessens, and in two to three weeks deadskin is absorbed and liquified, partially by enzymatic action andpartially by leukocytic digestion. This action is also accompanied bythe formation of serous exudate.

After the patient has been treated for shock and carefully planned fluidtherapy has been instituted to replace lost fluid, consideration isgiven to treatment of local areas. Two general methods are usuallyemployed: the closed method wherein mesh gauze bandages are applied; andthe open method which involves local care followed by placing a cradleover the body so that sheets are not in contact with burned areas. Inthe open or exposure method wounds are allowed to dry to form eschars orscabs. Thus after surgical cleansing, the depth and distribution ofburned areas determine whether the injury is best handled by exposure orby closed dressings. The determining factors for occlusive dressings arecase of achieving alleviation of burned areas during edema formation,need for immobilization to prevent cracking of eschar and the like. Ineither event topical application of one of several ointment bases, suchas petrolatum, containing a broad range of antibiotics and/or chemicalssuspended therein, for example, nitrofuranes, sulfonamides, etc., isWidely practiced.

SUMMARY OF THE INVENTION A particularly effective ointment which hasrecently come into use for the treatment of burns is bismuthtribromophenate in a nonsaponifiable oleaginous ointment base. Thebismuth tribromophenate ointment has been found to be particularlyeflicient in the treatment of burns, carbuncles, and similar skinproblems because it is capable of adsorbing fluid exudate. However ithas the disadvantage that even though it has been in use several years aprocess still does not exist for producing a stable suspension of thebismuth tribromophenate in the ointment base. It has, therefore, beennecessary to mix the bismuth tribromophenate in the oleaginous baselocally in each hospital shortly prior to use. In accordance with thepractice of this invention a stable suspension of bismuthtribromophenate in an oleaginous ointment base is provided.

DETAILED DESCRIPTION OF THE INVENTION Since for this use the ointmentbase must be nonabsorbable and nonsaponifiable, oleaginous ointmentbases are contemplated, such as white petrolatum, paraflin jelly,beeswax, and the like. A preferred base is paralfin jelly having amelting point of 433 C. The normal method of preparing onitments is toheat the oleaginous base, generally to its melting point, and then stirin the additional compounds, continuing to mix until the ointment hascooled. Bismuth tribromophenate however has a tendency to agglomerateduring the cooling stage so that it is practically impossible to make adependable suspension. Moreover the composition has no shelf life. Thebismuth tribromophenate settles to the bottom of the ointment base inthe first few months even under the best mixing procedures. Hence, if noburn case is admitted to a hospital for two or three months, theavailable ointment is not usable due to the settling of the bismuthtribromophenate.

Bismuth tribromophenate ointment is now the drug of choice for thetreatment of burns and for skin grafting because it is a nontoxic,nonabsorbable and profoundly analgesic and dependable antiseptic. Forthis reason it is preferred by many physicians even though fresh batchesmay have to be prepared after a patient is admitted to a hospital.However prior mixing delays relief to the patient, and also is a sourceof potential infection. In accordance with the practice of thisinvention it has been found that if a carefully observed homogenizationprocedure is followed at an elevated temperature below the decompositionpoint of the bismuth tribromophenate a stable suspension of the bismuthtribromophenate in the oleaginous ointment base can be made.

The preparation of the stable suspension contemplated herein isaccomplished by heating the oleaginous base to a temperature in therange of C. to the decomposition temperature, usually about 65 C.Preferably at a temperature of 40 C. to C. the bismuth tribromophenateis mixed with the ointment base by ordinary stirring means. At thiselevated temperature the composition is then subjected to incompletehomogenization. It has been found that if, at this temperature, morethan sixty percent by volume of the composition is homogenized, theointment is not completely effective, and indeed, if less than twentypercent of the material is homogenized, a stable suspension does notresult. The invention thus contemplates a stable suspension of two toten weight percent based on the total composition of bismuthtribromophenate dispersed in an oleaginous ointment base. The suspensionis rendered stable under incomplete homogenization conditions, at anelevated temperature below C., such that only a quantity in the range oftwenty to sixty percent of the composition is homogenized.

As is known in the art, the degree of homogenization is best controlledby the number of passes through a particular homogenizing device. Thusin a colloid mill requiring three passes for complete homogenization astable composition does not result when the bismuth tribromo-' phenatecomposition is passed through only once. In addition three passes hasbeen found to result in an unsatisfactory product.

The preparation of the stable emulsion contemplated herein can best beillustrated by means of the following specific examples which are, ofcourse, intended to be illustrative only since various modificationswill occur to those skilled in the art. Thus several methods ofachieving the desired degree of homogenization are available. In theexamples which follow five percent bismuth tribromophenate wasincorporated in petroleum jelly based on the weight of the totalcomposition.

Example 1 Using a water bath, 9,500 grams of the petrolatum base wereheated at a temperature of 45 C. to form a liquid melt. After thepetrolatum was melted 500 grams of bismuth tribromophenate were addedand the mixing was continued for five minutes. The product was kept atthe constant temperature of 45 C. during the mixing period. Afterthorough mixing the product was placed in a colloid mill. After partialhomogenization by virtue of one pass through the mill the product wascollected in a vessel, placed in the water bath and reheated to 45 C. Assoon as the composition reached this temperature, it was again runthrough the colloid mill. The second run through the colloid mill beingcompleted, the product was allowed to cool to approximately C. and thenpoured into suitably sized containers. This suspension of bismuthtribromophenate, known to be twenty to sixty percent homogenized, hasbeen found to be stable even after six months. At the end of this periodthe ointment remained suspended and consistent in analysis.

Whereas the desired degree of homogenization is in the range of twentyto sixty percent by volume, it has been found that the ideal extent ofhomogenization is thirty-five percent by volume. Bismuth tribromophenatethus prepared is available to adsorb the serum exudate, with the basefree to allow seepage of the serum. It is emphasized however that evenwith the proper degree of homogenization, if the homogenization is notconducted at the required elevated temperature a stable suspension stilldoes not result. Thus, if petrolatum and bismuth tribromophenate arepassed through a homogenizer under conditions resulting in twenty tosixty percent homogenization but at a temperature below C., theresulting product is unsatisfactory. Without being bound by any theoryof this invention, it appears that if a shearing of all the bismuthtribromophenate particles takes place they are no longer effective oravailable for medication and adsorption. Their therapeutic andadsorption properties are reduced. On the other hand if an insufficientquantity of the particles is subjected to the shearing action a stablecomposition does not result. Stated somewhat differently twenty to sixtypercent of the particles in the bismuth tribromophenate ointment must bein the size range of less than two microns. The dispersion is thenstable. This can be illustrated by the following examples using the samequantities of materials as in Example 1, but different degrees ofhomogenization.

Example 2 A mixture of bismuth tribromophenate prepared in accordancewith Example 1 at a temperature of C. was homogenized in a colloid mill,preparing an ultimate ointment resulting in a dgree of homogenization ofabout fifteen percent. There was some agglomeration on standing aftercooling, and within six months bismuth tribromophenate settled to thebottom of the container. The resulting product was better in appearancethan one made by mere stirring, but the ointment was unstable.

Example 3 Following the procedure of Example 1 an ointment was prepared.However at 45 C. the composition was homogenized in a colloid mill underconditions producing a degree of homogenization of between sixty andeighty percent. It was found that the increased degree of homogenizationdid not improve the suspension. Rather the increased degree of shearingof bismuth tribromophenate particles reduced the therapeutic efiiciencyof the result- 4 ing ointment as an antiseptic and adsorbent, reducingits analgesic properties.

Example 4 Following the procedure of Example 1 but using 9,800 grams ofpetrolatum and 200 grams of bismuth tribromophenate a composition wasmade known to be thirty-five percent homogenized. The ointment was usedat Vanderbilt University Hospital in the treatment of burns withexcellent results.

It can thus be seen that by the practice of this invention an improvedointment containing bismuth tribromophenate can be rendered stablewithout losing its therapeutic values. The provision of this ointment instable form makes it available at anytime, even after long standing, forthe treatment of a variety of skin problems requiring an emollientcontaining a nonabsorbable antiseptic which is capable of adsorbingfluid exudate. It will be understood of course that minor quantities,say, one-half to five percent of other medicinals can be incorporated inthe composition as in known in the art. In addition modifiers, forinstance, mineral oil, can also be added to the ointment base. These andother variations will occur to those skilled in this field. Suchramifications are deemed to be within the scope of this invention.

What is claimed is:

1. A stable suspension for the treatment of burns, consisting of bismuthtribromophenate in a nonsaponifiable, oleaginous ointment base notabsorbed into the skin, said suspension containing two to ten weightpercent based on the composition of bismuth tribromophenate dispersedtherein, the suspension rendered stable by incomplete homogenization ata temperature in the range of 40 C. to 65 C. such that at saidtemperature only a quantity in the range of twenty to sixty volumepercent of the bismuth tribromophenate particles in the ointment arehomogenized to a size range of less than two microns.

2. The composition of claim 1 wherein the oleaginous ointment base isparaffin jelly having a melting point of 433 C. and wherein the bismuthtribromophenate is dispersed therein in an amount of five weightpercent.

3. The composition of claim 1 having two weight percent of the bismuthtribromophenate dispersed therein.

4. The composition of claim 1, rendered stable by the homogenization ofthirty to forty volume percent thereof.

5. A process for the preparation of a stable suspension for thetreatment of burns, consisting of bismuth tribromophenate containing twoto ten weight percent bismuth tribromophenate in a nonsaponifiable,oleaginous ointment gase which comprises heating the oleaginous ointmentbase to a temperature in the range of 40 C. to about 65 C., mixing thebismuth tribromophenate in the oleaginous base, and at said temperaturehomogenizing the mixture until at least twenty percent but not more thansixty percent by volume of the bismuth tribromophenate particles in theointment are homogenized to a size range of less than two microns.

6. The process of claim 5 wherein the homogenization temperature is 40C. to 50 C.

7. The process of claim 5 wherein the degree of homogenization isthirty-five percent by volume.

References Cited Wilson et al., Textbook of Organic Medicinal andPharmaceutical Chemistry, fourth edition, 1962, p. 197.

Sagarin, Cosmetics, Science and Technologly, 1966, pp. 998-999,1002-1003, 1020-1031.

Remingtons Practice of Pharmacy, 12th edition, 1961, pp. 408-410.

ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner

